Jorgensen, Roberta A.

Background and Aims: Fatigue is a common symptom of primary biliary cirrhosis (PBC), and is associated with an impaired quality of life. Study Question: No studies have assessed the use of modafinil in fatigue related to PBC in a controlled manner. Study Design, Measures, and Outcomes: A randomized, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of modafinil for the treatment of fatigue in PBC. Forty patients were randomized to modafinil (n = 20) or placebo (n = 20) for 12 weeks. A verbal report of fatigue for at least 6 months was required for enrollment. Modafinil was administered at 100 mg by mouth once daily; a change by 50 mg every 2 weeks (maximum: 200 mg once daily) was allowed, depending on the subject's response to treatment. The primary outcome was defined as a ≥50% improvement in fatigue severity [quantified by the Fisk Fatigue Impact Scale (FFIS)] after 12 weeks of treatment, compared with baseline values. Results: Thirty-three PBC patients completed the study. After 12 weeks of therapy, only 5 patients had a ≥50% reduction in FFIS scores: 3 patients (17.6%) in the modafinil arm and 2 (12.5%) in the placebo arm (P = 1.00). Change in median FFIS score was not statistically different between patients in the 2 treatment groups (P = 0.36). Modafinil was associated with minimal adverse events (headaches, diarrhea, and rash). Conclusions: In patients with PBC who have fatigue, treatment with modafinil for 12 weeks was safe and fairly well tolerated; however, it did not result in beneficial effects on fatigue compared with patients treated with placebo (CONSORT Table 1). ClinicalTrials.gov identifier NCT00943176.

Introduction Significant impairments in health-related quality of life (HRQL) in patients with non-alcoholic fatty liver disease have been previously described. The disease-specific HRQL among patients with non-alcoholic steatohepatitis (NASH), however, remains unknown. Aim To determine the degree of construct validity of the Chronic Liver Disease Questionnaire (CLDQ) in adults with NASH. Methods Participants referred for the evaluation of histology-proven NASH at Mayo Clinic, Rochester, between 1996 and 2000, were evaluated. HRQL assessment by the Short-Form 36 (SF-36) Health Survey and CLD) was performed. The primary outcome was to determine the level of correlation between overall and subscale scores for the CLDQ and SF-36 instruments. Results Among 79 participants (70%) with NASH completing both questionnaires (mean age, 51.2 years with 64% female gender), excellent reliability was noted for the CLDQ instrument. Significant reductions in all SF-36 domains (p<0.05 for all) including PCS and MCS scores (p<0.02 for both) among participants with NASH compared with normative data from an age-matched and sex-matched US general population sample was observed. Highly significant correlations were observed between overall CLDQ score with SF-36 PCS (r=0.82, p<0.0001) and SF-36 MCS (r=0.67, p<0.0001) scores. Similar degrees of correlation were observed between relevant subscales of the CLDQ and SF-36 as well. Discussion The CLDQ has excellent reliability and validity of construct for HRQL assessment in adults with NASH when compared with the SF-36. Future investigations among participants with NASH require assessing the responsiveness of the CLDQ to medical therapies and disease progression.

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week, open-label pilot study to investigate the efficacy and safety of 550 mg of oral rifaximin twice daily. The primary end point was serum alkaline phosphatase (ALK) at 12 weeks. Secondary end points included (1) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; (2) fatigue impact scale, chronic liver disease questionnaire, and short form health survey (SF-36) scores; and (3) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years; 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range, 275–520 IU/mL). After 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL; P = 0.47) or any of the secondary biochemical end points (all P > 0.05). Similarly, there were no significant changes in fatigue impact scale, chronic liver disease questionnaire, or SF-36 scores (all P > 0.05). Three patients withdrew from the study due to AEs; 4 others reported mild AEs but completed the study. In conclusion, although some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, seems inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC.

Summary Background Emerging data suggest that oral antibiotics may have therapeutic effects in primary sclerosing cholangitis ( PSC ), but published studies are limited. Aims To investigate the safety and efficacy of oral vancomycin and metronidazole in patients with PSC . Methods Thirty‐five patients with PSC were randomised in a double‐blind manner into four groups: vancomycin 125 mg or 250 mg four times/day, or metronidazole 250 mg or 500 mg three times/day for 12 weeks. The primary endpoint was decrease in alkaline phosphatase ( ALK ) at 12 weeks. Secondary end points included serum bilirubin and Mayo PSC risk score; pruritus; and adverse effects ( AE s). Nonparametric tests were used for analysis. Results The primary endpoint was reached in the low‐dose (−43% change in ALK , P = 0.03) and high‐dose (−40%, P = 0.02) vancomycin groups, with two patients in the former experiencing ALK normalisation. Bilirubin decreased significantly in the low‐dose metronidazole group (−20%, P = 0.03) and trended towards significance in the low‐dose vancomycin group (−33%, P = 0.06). Mayo PSC risk score decreased significantly in the low‐dose vancomycin (−0.55, P = 0.02) and low‐dose metronidazole group (−0.16, P = 0.03). Pruritus decreased significantly in the high‐dose metronidazole group (−3.4, P = 0.03). AE s led to medication discontinuation in six patients, four of whom were receiving metronidazole. Conclusions Both vancomycin and metronidazole demonstrated efficacy; however, only patients in the vancomycin groups reached the primary endpoint, and with less adverse effects. Larger, longer‐term studies are needed to further examine the safety and efficacy of antibiotics as a potential treatment for patients with primary sclerosing cholangitis ( clinicaltrials.gov NCT01085760 ).

AbstractBackgroundBiochemical tests have been recommended as endpoints for clinical trials in primary biliary cirrhosis (PBC) because the use of liver transplantation and death as endpoints in ursodeoxycholic acid (UDCA) therapeutic trials is unfeasible. The best inclusion criteria cut‐off values and cut‐off for demonstrating treatment success have not been defined.AimOur aim was to determine the optimal biochemical values for patient inclusion and to define values for treatment success in therapeutic trials.MethodsWe performed a retrospective review of 73 patients with PBC treated with UDCA followed over 36 months. Following one year of UDCA therapy, the likelihood of developing clinical endpoints of varices, ascites, encephalopathy, death or transplantation over the ensuing two years, based on degrees of elevation of biochemical markers, was analyzed using chi‐square or Fisher's exact test.ResultsPatients with ALP≥2 X upper limit of normal (ULN) had a 2‐fold greater likelihood of developing endpoints compared to patients with lower values (23% versus 11%), (p < 0.05). Patients with bilirubin > 1 mg/dL were 4 times more likely to develop endpoints compared to those with lower values (33% versus 8%), (p = 0.02). These values help identify the patient population for adjunctive therapy trials. Patients with ALP ≤1.67 X ULN and bilirubin ≤1mg/dL demonstrated the least likelihood of reaching adverse clinical endpoints and can be used to define treatment success.ConclusionOptimal ALP and Bilirubin levels can be used as appropriate biochemical criteria for patient selection and defining treatment success in future clinical trials in patients with PBC.